JP2006516632A - Quinoline derivatives as NK-2 and NK-3 receptor antagonists - Google Patents

Abstract

Disclosed are compounds of formula (I), or pharmaceutically acceptable salts thereof, which are NK2 and NK3 receptor antagonists and are useful in the treatment of respiratory diseases.
[Chemical 1]

Description

Detailed Description of the Invention

The present invention relates to novel compounds, particularly novel quinoline derivatives, methods for preparing such compounds, pharmaceutical compositions containing such compounds, and the use of such compounds in medicine.

BACKGROUND OF THE INVENTION The mammalian peptide neurokinin B (NKB) belongs to the tachykinin (TK) peptide family that also includes substance P (SP) and neurokinin A (NKA). Pharmacological and molecular biological evidence indicates the presence of _three subtypes of the TK receptor (NK ₁ , NK ₂ and NK ₃ ), while NKB preferentially binds to the NK ₃ receptor, It also recognizes the other two receptors with lower affinity (Maggi et al, 1993, J. Auton. Pharmacol., 13, 23-93).
Selective peptidic NK ₃ receptor antagonists are known (Drapeau, 1990 Regul. Pept. , 31, 125-135), findings using peptidic NK ₃ receptor agonists, NKB is, NK ₃ receptor Activation suggests that it has an important role in the regulation of neural input in the airway, skin, spinal cord and nigrostriatal pathways (Myers and Undem, 1993, J. Physiol., 470, 665-679; Counture et al., 1993, Regul. Peptides, 46, 426-429; Mccarson and Krause, 1994, J. Neurosci., 14 (2), 712-720; Arenas et al. 1991, J Neurosci., 11, 2332-8). However, due to the peptide-like nature of the known antagonists, they appear too unstable to act as practical therapeutic agents from a metabolic point of view.

International Patent Application Publication No. WO 00/58307 describes a series of aryl fused 2,4-disubstituted pyridines, such as naphthyridine derivatives, which are described as exhibiting biological activity as NK ₃ receptor antagonists. The
The compound of the present invention is a quinoline derivative. Other quinoline derivatives have been previously described as selective NK ₃ antagonists. For example, International Patent Application Publication Nos. WO 95/32948 and WO 96/02509 describe a series of selective and potent NK ₃ receptor antagonists.

International Patent Application Publication No. WO 00/64877 describes a series of 2-aminoquinoline carboxamides as neurokinin receptor ligands.
International Patent Application Publication No. WO 00/58303 describes a series of 4-substituted quinoline derivatives and describes them as NK ₃ and / or GABA (A) receptor ligands. Such compounds are characterized by the presence of a nitrogen-containing heterocyclic group at the C (4) position of the quinoline ring.
International Patent Application Publication Nos. WO 97/21680, WO 98/52942, WO 00/31037, WO 00/31038, WO 02/38547, WO 02/38548, WO 02/43734, WO 02/44154, and WO 02/44165 are combined NK ₃ and NK describe compounds which have biological activity as _receptor antagonists.

The inventors have now found a new class of non-peptide NK ₃ antagonists that are much more stable and have potential therapeutic utility than known peptide NK ₃ receptor antagonists from a metabolic perspective. It was. These compounds also have NK ₂ antagonist activity and therefore have potential applications in the prevention and treatment of a wide variety of clinical conditions characterized by excessive stimulation of tachykinin receptors, especially NK ₃ and NK _2. It is believed that there is.

  These conditions include respiratory diseases such as chronic obstructive pulmonary disease (COPD), asthma, airway hyperreactivity, cough; inflammatory diseases such as inflammatory bowel disease, psoriasis, connective tissue inflammation, osteoarthritis, rheumatoid arthritis and Inflammatory pain; neurological inflammation or peripheral neuropathy, allergies such as eczema and rhinitis; eye diseases such as ocular inflammation, conjunctivitis, spring conjunctivitis, etc .; skin diseases, skin disorders and pruritus such as skin rash and redness, contact skin Inflammation, atopic dermatitis, urticaria and other eczema-like dermatitis; adverse immunological reactions such as transplant rejection and disorders related to immune enhancement or suppression such as systemic lupus erythematosus; gastrointestinal (GI) Disorders and diseases of the GI tract, eg disorders associated with neuronal modulation of the viscera, eg ulcerative colitis, Crohn's disease, irritable bowel syndrome (IB ), Gastro-exophageous reflex disease (GERD); urinary incontinence and bladder function impairment; renal disorder; increased blood pressure following preeclampsia in pregnancy, proteinuria, coagulopathy and peripheral and cerebral edema , "First state").

  Some of these compounds also exhibit CNS activity and thus central nervous system disorders such as anxiety, depression, psychosis and schizophrenia; neurodegenerative disorders such as AIDS-related dementia, Alzheimer's type senility Dementia, Alzheimer's disease, Down's syndrome, Huntington's disease, Parkinson's disease, movement disorders, and convulsive disorders (eg, sputum); demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis and other nerves Pathological disorders such as diabetic neuropathy, AIDS-related neuropathy, chemotherapy-induced neuropathy and neuralgia; epilepsy disorders such as alcoholism; stress-related disabilities; reflex sympathetic dystrophy such as shoulder / hand syndrome; Mood disorders; eating disorders (eg, food intake disorders); fibrosis and collagen disease For example, scleroderma and eosinophilic cirrhosis; impaired blood flow caused by vasodilation and vasospasm diseases such as angina, migraine and Reynaud's disease and, for example, any of the above conditions It is believed to be particularly useful in the treatment of contributory or related pain or nociceptive demands, in particular pain transmission in migraine (hereinafter referred to as “second condition”).

The compounds of formula (I) are also useful as diagnostic tools for assessing the extent to which neurokinin-3 and neurokinin-2 receptor activity (normal, overactive or underactive) is involved in patient symptoms it is conceivable that.
Certain compounds of the present invention have also surprisingly been found to exhibit advantageous pharmacochemical properties.

Detailed Description of the Invention According to the present invention, the compound of formula (I):

[Where:
R ₁ is H or substituted or unsubstituted (C _1-6 ) alkyl;
R ₂ is substituted or unsubstituted aryl, (C _3-7 ) cycloalkyl, or heterocycle;
R ₃ is H or substituted or unsubstituted (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, aryl or heterocycle;
A is NR ₈ or O;
R ₈ is H or substituted or unsubstituted (C _1-6 ) alkyl;
R ₄ is substituted or unsubstituted phenyl;
R ₅ is H or from a list consisting of alkyl, alkenyl, aryl, alkoxy or hydroxylated derivatives thereof, hydroxy, halogen, nitro, cyano, carboxy, alkylcarboxy, alkylcarboxyalkyl, haloalkyl, amino or mono- or dialkylamino Up to three independently selected substituents; or R ₅ represents a bridging moiety arranged to bridge two adjacent ring atoms, wherein the bridging moiety is alkyl or dioxy Including alkylene;
R ₆ is H or halo;
R ₇ is oxo;
n is 1-4]
Or a pharmaceutically acceptable salt or solvate thereof.

Preferably R ₁ is methyl.
Suitably R ₂ is substituted or unsubstituted aryl or (C _3-7 ) cycloalkyl. Preferably R ₂ is substituted or unsubstituted phenyl or cyclohexyl. Most preferably R ₂ is unsubstituted cyclohexyl.

Preferably R ₃ is (C _1-6 ) alkyl or heterocyclic. Methyl is the most preferred R ₃ group. Other most preferred R ₃ groups are substituted and unsubstituted morpholino, piperazine, pyrrole, pyrrolidine, piperidine, thiophene, imidazole, and pyrazole. Particularly preferred groups are substituted and unsubstituted morpholino, piperazine, piperidine and pyrrolidine.

Preferably R ₈ is H or methyl.
Preferably, R ₄ is phenyl substituted with 1 to 3 fluorines. Most preferably R ₄ is 3,5-difluorophenyl or 4-fluorophenyl.
Preferably R ₅ is H or fluoro.
Preferably R ₆ is H or fluoro.
Preferably n is 1.

Preferred compounds of formula (I) of particular interest as agents useful in the treatment and / or prevention of conditions characterized by overstimulation of tachykinin receptors, in particular NK ₃ and NK ₂ , are:
2- (3,5-Difluoro-phenyl) -6-fluoro-3- {4- [2- (4-methyl-piperazin-1-yl) -2-oxo-ethyl] -3-oxo-piperazine-1 -Ylmethyl} -quinoline-4-carboxylic acid ((S) -1-cyclohexyl-ethyl) -amide;
2- (3,5-Difluoro-phenyl) -6-fluoro-3- [3-oxo-piperidin-1-yl-ethyl) -piperazin-1-ylmethyl] -quinoline-4-carboxylic acid ((S)- 1-cyclohexyl-ethyl) -amide;
6-Fluoro-2- (4-fluoro-phenyl) -3- [4- (2-morpholin-4-yl-2-oxo-ethyl) -3-oxo-piperazin-1-ylmethyl] -quinoline-4- Carboxylic acid ((S) -1-cyclohexyl-ethyl) -amide;
6-Fluoro-2- (4-fluoro-phenyl) -3- {4- [2- (4-methyl-piperazin-1-yl) -2-oxo-ethyl] -3-oxo-piperazin-1-ylmethyl } -Quinoline-4-carboxylic acid ((S) -1-cyclohexyl-ethyl) -amide; and 6-fluoro-2- (4-fluoro-phenyl) -3- [3-oxo-4- (2-oxo) -2-pyrrolidin-1-yl-ethyl) -piperazin-1-ylmethyl] -quinoline-4-carboxylic acid ((S) -1-cyclohexyl-ethyl) -amide; or a pharmaceutically acceptable salt thereof.

［式中、Ｒ_１、Ｒ_２、Ｒ_４、Ｒ_５およびＲ_６は式（Ｉ）に関して定義されたとおりであり、Ｘは基

（式中、Ｒ_７およびＲ_３は式（Ｉ）に関して定義されたとおりである）］
で示される立体化学を有する化合物を包含する。 The compound of formula (I) may have at least one asymmetric center, for example a carbon atom labeled with an asterisk ( ^* ) in the compound of formula (I), and thus one or more stereoisomers It may be present in the form. The invention extends to all such stereoisomeric forms and mixtures thereof including racemates. In particular, the present invention provides that the carbon atom to which an asterisk is added in formula (I) is represented by

Wherein R ₁ , R ₂ , R ₄ , R ₅ and R ₆ are as defined for formula (I) and X is a group

In which R ₇ and R ₃ are as defined for formula (I)]
The compound which has the stereochemistry shown by these is included.

The compound of formula (I) or salt or solvate thereof is preferably in pharmaceutically acceptable or substantially pure form. Depending on the pharmaceutically acceptable form, it includes, among other ingredients, pharmaceutically acceptable levels of purity that are considered toxic at normal dosage levels, with the exception of conventional pharmaceutical additives such as diluents and carriers, among others. It means no.
The substantially pure form is generally at least 50% (excluding conventional pharmaceutical additives), preferably 75%, more preferably 90%, even more preferably 95% of a compound of formula (I) or a salt thereof Or it will contain solvates.

One preferred pharmaceutically acceptable form is the crystalline form, including such form in a pharmaceutical composition. In the case of salts and solvates, the additional ionic and solvent moieties must not be toxic.
Suitable salts are pharmaceutically acceptable salts.
Suitable pharmaceutically acceptable salts include conventional pharmaceutical acids such as maleic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, fumaric acid, salicylic acid, citric acid, lactic acid, mandelic acid, tartaric acid, succinic acid. Includes acid addition salts with acids, benzoic acid, ascorbic acid and methanesulfonic acid.

Suitable pharmaceutically acceptable salts include salts of the acidic moiety of the compound of formula (I), for example salts of carboxy groups or phenolic hydroxy groups, if present.
Suitable salts of the acidic moiety are metal salts such as aluminum, alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts such as lower alkyl amines. Salts with, for example, triethylamine, hydroxyalkylamines, such as 2-hydroxyethylamine, bis- (2-hydroxyethyl) -amine or tri- (2-hydroxyethyl) -amine, cycloalkylamines, such as bicyclohexylamine Or procaine, dibenzylpiperidine, N-benzyl-β-phenethylamine, dehydroabiethylamine, N, N′-bisdehydroabiethylamine, glucamine, N-methylglucamine or a pyridine type salt It includes, for example, pyridine, collidine, salts with quinine or quinoline.

Suitable solvates are pharmaceutically acceptable solvates.
Suitable pharmaceutically acceptable solvates include hydrates.
The term “alkyl” or (C _1-6 ) alkyl (unless otherwise stated) when used alone or when forming part of another group (eg, an “alkoxy” group) Includes straight or branched chain alkyl groups containing 1 to 6 carbon atoms, including, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl groups.

The term “alkenyl” or (C _1-6 ) alkenyl (unless otherwise stated), when used alone or when forming part of another group, at least one double C═C Includes straight or branched unsaturated carbon chains containing bonds and containing 2-6 carbon atoms.
The term “carbocycle” refers to cycloalkyl and aryl rings.
The term “cycloalkyl” includes groups having 3 to 7 ring carbon atoms.

Suitable substituents for any (C _1-6 ) alkyl, (C _1-6 ) alkenyl and (C _3-7 ) cycloalkyl groups are hydroxy, halogen, nitro, cyano, carboxy, amino, mono- and Selected from the group consisting of di- (C _1-6 ) alkylaminocarboxamide, sulfonamide, (C _1-6 ) alkoxycarbonyl, trifluoromethyl, acyloxy, (C _3-7 ) cycloalkyl, aryl and heterocycle Includes up to 3 substituents.
The term “aryl” means phenyl and naphthyl, preferably halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxyalkyl, hydroxy, amino, nitro, cyano, carboxy, alkoxycarbonyl, unless stated otherwise, Includes phenyl containing up to 5, preferably up to 3, substituents selected from alkoxycarbonylalkyl, alkylcarbonyloxy, or alkylcarbonyl groups.

The term “heterocycle” includes aromatic heterocycles containing from 5 to 12 ring atoms, suitably 5 or 6, in each ring up to 4 heterocycles selected from S, O or N. Includes groups containing atoms.
Synthetic terms such as “alkylcarboxy”, “cycloalkylalkyl” and the like refer to a component of a compound that includes two linking groups, the group named after the term being a linking group, so that “alkylcarboxy” "Means (alkyl) -COO-, while" cycloalkylalkyl "means (cycloalkyl)-(alkyl)-.

Unless stated to the contrary, suitable substituents for any heterocyclic group include up to 4 substituents selected from the group consisting of alkyl, alkoxy, aryl and halogen, or are attached to them. Any two substituents on adjacent carbon atoms may form an aryl group, preferably a benzene ring, together with the aryl group represented by the two substituents. The carbon atom itself may be substituted or unsubstituted.
As used herein, the term “halogen” refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine or bromine.

As used herein, the term “acyl” includes acid residues, particularly carboxylic acid residues such as alkyl- or aryl-carbonyl groups.
Certain reagents are abbreviated herein. DCC represents dicyclohexylcarbodiimide, DMAP represents dimethylaminopyridine, DIEA represents diisopropylethylamine, and EDC represents 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. HOBt represents 1-hydroxybenzotriazole, THF represents tetrahydrofuran, DIEA represents diisopropylethylamine, DEAD represents diethyl azodicarboxylate, PPh ₃ represents triphenylphosphine, DIAD represents diisopropyl azodicarboxylate, DME indicates dimethoxyethane, DMF indicates dimethylformamide, NBS indicates N-bromosuccinimide, Pd / C indicates palladium catalyst on carbon, PPA indicates polyphosphoric acid, DPPA indicates diphenylphosphoryl azide , BOP represents benzotriazol-1-yloxy-tris (dimethyl-amino) phosphonium hexafluorophosphate, HF represents hydrofluoric acid, TEA represents triethylamine, TFA represents trifluoro It represents oloacetic acid, and PCC represents pyridinium chlorochromate.

［式中、Ｒ’_４、Ｒ’_５、Ｒ’_６およびＸ’は各々、式（Ｉ）または（Ｉｂ）に関して上記したＲ_４、Ｒ_５、Ｒ_６およびＸであるか、または各々、Ｒ_４、Ｒ_５、Ｒ_６およびＸに変換可能な基である］
で示される化合物またはその活性誘導体を式（ＩＩＩ）：

［式中、Ｒ’_１およびＲ’_２は式（Ｉ）に関して定義したＲ_１およびＲ_２であるか、または各々、Ｒ_１およびＲ_２に変換可能な基もしくは原子である］
で示される化合物と反応させて、式（Ｉｃ）：

［式中、Ｒ’_１、Ｒ’_２、Ｘ’、Ｒ’_４、Ｒ’_５およびＲ’_６は上記のとおりである］
で示される化合物を形成させ、その後、下記の任意の工程：
（ｉ）必要に応じて、Ｒ’_１、Ｒ’_２、Ｘ’、Ｒ’_４、Ｒ’_５およびＲ’_６のいずれか１つを各々、Ｒ_１、Ｒ_２、Ｘ、Ｒ_４、Ｒ_５およびＲ_６に変換して式（Ｉ）の化合物を得る；
（ｉｉ）式（Ｉ）の化合物を式（Ｉ）の別の化合物に変換する；および
（ｉｉｉ）式（Ｉ）の化合物の塩および／またはその溶媒和物を調製する
の１以上を行うことを特徴とする。 The present invention also provides, in one aspect, a process for preparing a compound of formula (I) or a salt thereof and / or a solvate thereof, wherein the process comprises formula (II):

Wherein R ′ ₄ , R ′ ₅ , R ′ ₆ and X ′ are each R ₄ , R ₅ , R ₆ and X as described above with respect to formula (I) or (Ib), or each is R ₄ , a group convertible to R ₅ , R ₆ and X]
Or the active derivative thereof is represented by the formula (III):

[Wherein R ′ ₁ and R ′ ₂ are R ₁ and R _{2 as} defined for formula (I), or are groups or atoms, respectively, convertible to R ₁ and R ₂ ]
Is reacted with a compound of formula (Ic):

[Wherein R ′ ₁ , R ′ ₂ , X ′, R ′ ₄ , R ′ ₅ and R ′ ₆ are as described above]
And then the following optional steps:
(I) As necessary, any one of R ′ ₁ , R ′ ₂ , X ′, R ′ ₄ , R ′ ₅ and R ′ ₆ is R ₁ , R ₂ , X, R ₄ , R Conversion to ₅ and R ₆ to give a compound of formula (I);
Performing one or more of (ii) converting a compound of formula (I) to another compound of formula (I); and (iii) preparing a salt of the compound of formula (I) and / or a solvate thereof. It is characterized by.

Suitable groups that can be converted to other groups include protected forms of the groups.
Suitably R ′ ₁ , R ′ ₂ , X ′, R ′ ₄ , R ′ ₅ and R ′ ₆ are each R ₁ , R ₂ , X, R ₄ , R ₅ and R ₆ or protected thereof Indicates the form.
It is preferred if the compound of formula (II) is present as an active derivative.
Suitable active derivatives of compounds of formula (II) are groups or atoms with different carboxy groups of compounds of formula (II) or compounds of formula (II), such as acyl halides, preferably chlorides, or acyl azides. Alternatively, it is a temporary active form of a derivative that replaces a carboxylic anhydride.

  Other suitable active derivatives are mixed anhydrides formed between the carboxyl moiety of the compound of formula (II) and the alkyl chloroformate; active esters such as cyanomethyl esters, thiophenyl esters, p-nitrophenyl esters P-nitrothiophenyl ester, 2,4,6-trichlorophenyl ester, pentachlorophenyl ester, pentafluorophenyl ester, N-hydroxy-phthalimide ester, N-hydroxypiperidine ester, N-hydroxysuccinimide ester, N-hydroxybenzo Alternatively, the carboxyl group of the compound of formula (II) may be activated with carbodiimide or N, N′-carbonyldiimidazole.

  The reaction between the compound of formula (II) or an active derivative thereof and the compound of formula (III) is carried out under conventional conditions appropriate for the particular compound selected. In general, when the compound of formula (II) is present as an active derivative, the reaction is carried out using the same solvent and conditions used to prepare the active derivative, preferably the active derivative Is prepared in situ prior to formation of the compound of formula (Ic), after which the compound of formula (I) or a salt thereof and / or a solvate thereof is prepared.

For example, the reaction between an active derivative of a compound of formula (II) and a compound of formula (III) is: (a) First, an acid chloride is prepared, then the chloride and the compound of formula (III) And in a suitable aprotic solvent such as dimethylformamide (DMF) at −70 to 50 ° C. (preferably −10 to 20 ° C.) in the presence of an inorganic base or an organic base. Or (b) in the presence of a suitable condensing agent such as N, N′-carbonyldiimidazole (CDI) or carbodiimide, such as dicyclohexylcarbodiimide (DCC) or N-dimethylaminopropyl-N′-ethylcarbodiimide, Preferably, N-hydroxybenzotriazole (HOBT), or O-benzoto to maximize yield and avoid racemization steps In the presence of riazol-1-yl-N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU), a mixture of an aprotic solvent, for example acetonitrile (MeCN) and tetrahydrofuran (THF), for example , 1: 9 to 7: 3 (MeCN: THF) in a volume ratio mixture at any temperature that provides a suitable rate of formation of the desired product, e.g., -70-50 ° C, preferably -10-10 By treating a compound of formula (II) with a compound of formula (III) at 25 ° C., eg 0 ° C.
You may go.

［式中、Ｒ’_１、Ｒ’_２、Ｘ’、Ｒ’_４、Ｒ’_５およびＲ’_６は上記のとおりである。］ A preferred reaction is illustrated in Scheme 1 shown below.
Scheme 1

[Wherein, R ′ ₁ , R ′ ₂ , X ′, R ′ ₄ , R ′ ₅ and R ′ ₆ are as described above]. ]

When the corresponding alkyl (eg methyl or ethyl) ester of compound (II) is utilized, hydrolysis to compound (II) is required prior to conversion to compound (Ic) in Scheme 1. Such hydrolysis can be performed under acidic conditions, for example, at 30 to 100 ° C. under 10-36% hydrochloric acid.
A compound of formula (Ic) may be converted to a compound of formula (I) or a compound of formula (I) may be converted to another compound of formula (I) by interconversion of appropriate substituents. It will be clear that it is good. Thus, certain compounds of formulas (I) and (Ic) are useful intermediates in the formation of other compounds of the invention.

Accordingly, in a further aspect, the invention provides that at least one of R ′ ₁ , R ′ ₂ , X ′, R ′ ₄ , R ′ ₅ and R ′ ₆ is each R ₁ , R ₂ , X, R ₄ , R Converting a compound of formula (Ic) above that is not ₅ or R ₆ thereby providing a compound of formula (I); then optionally following the optional steps:
Performing one or more of (i) converting a compound of formula (I) to another compound of formula (I); and (ii) preparing a salt of the compound of formula (I) and / or a solvate thereof. A process for the preparation of a compound of formula (I) or a salt thereof and / or a solvate thereof is provided.

Suitably, in the compound of formula (Ic), the variables R ′ ₁ , R ′ ₂ , X ′, R ′ ₄ , R ′ ₅ and R ′ ₆ are each R ₁ , R ₂ , X, R ₄ , R ₅ and R ₆ or they are protected forms thereof.
The above transformations, protections and deprotections are performed using suitable conventional reagents and conditions and are discussed further below.

［式中、Ｒ’_４、Ｒ’_５およびＲ’_６は上記のとおりであり、Ｌ_１はハロゲン原子、例えば、臭素原子である］
で示される化合物または対応するアルキル（例えば、メチルまたはエチル）エステルを式（Ｖ）：

［式中、Ｒ_３およびＲ_７は、式（Ｉ）に関して定義されたとおりである］
で示される化合物またはその保護形態と反応させることによって調製される。 A chiral compound of formula (III) in which R ₂ is a C ₅ or C ₇ cycloalkyl group, R ₃ is methyl and R ₁ is H is described in J. Org. Chem. (1996), 61 (12) , 4130-4135. Chiral compounds of formula (III) in which R ₂ is phenyl, R ₃ is isopropyl and R ₁ is H are described, for example, in Tetrahedron Lett. (1994), 35 (22), 3745-6 It is a known compound.
The compounds of formula (III) are known commercially available compounds or they are known methods or methods similar to those used for the preparation of known compounds, for example Liebigs Ann. Der Chemie, (1936) , 523, 199 can be prepared from known compounds.
In some embodiments of the invention, the compound of formula (II) or the corresponding alkyl (eg methyl or ethyl) ester is of formula (IV):

[Wherein R ′ ₄ , R ′ ₅ and R ′ ₆ are as described above, and L ₁ is a halogen atom, for example, a bromine atom]
Or a corresponding alkyl (eg, methyl or ethyl) ester of formula (V):

[Wherein R ₃ and R ₇ are as defined for formula (I)]
Or a protected form thereof.

Suitably, the reaction between the compound of formula (IV) or the corresponding alkyl (eg methyl or ethyl) ester and (V) is carried out under conventional amination conditions, eg L ₁ is bromine When atomic, the reaction is conveniently performed in an aprotic solvent such as tetrahydrofuran or dimethylformamide at any temperature that provides a suitable rate of formation of the desired product, usually at ambient temperature. Preferably, the reaction is carried out in the presence of triethylamine (TEA) or K ₂ CO ₃ .

  The compounds of formula (V) are known commercial compounds or they are methods analogous to those used for the preparation of known compounds, for example the Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; Advanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992; J. Heterocyclic Chem. (1990), 27, 1559; Synthesis (1975), 135, Bioorg. Med. Chem. Lett (1997), 7, 555 or Protective Groups in Organic Synthesis (second edition), Wiley Interscience, (1991) or other methods listed therein.

［式中、Ｒ’_４、Ｒ’_５およびＲ’_６は式（ＩＩ）に関して上記したとおりである］
で示される化合物または対応するアルキル（例えば、メチルまたはエチル）エステルの適当なハロゲン化によって調製されうる。 The compound of formula (IV) or the corresponding alkyl (eg methyl or ethyl) ester is of formula (VI):

[Wherein R ′ ₄ , R ′ ₅ and R ′ ₆ are as described above for formula (II)].
Or a corresponding alkyl (eg, methyl or ethyl) ester may be prepared by appropriate halogenation.

A suitable halogenating reagent is a conventional reagent depending on the nature of the halogen atom required, for example when L ₁ is bromine, a preferred halogenating reagent is N-bromosuccinimide (NBS).

Halogenation of the compound of formula (VI) or the corresponding alkyl (eg methyl or ethyl) ester is suitably carried out under conventional conditions, for example bromination is carried out by carbon tetrachloride CCl ₄ , or 1 , 2-dichloroethane or CH ₃ CN in an inert solvent at any temperature that provides a suitable rate of formation of the desired product, suitably at an elevated temperature such as 60 ° C. to 100 ° C., for example At 80 ° C. by treatment with NBS; preferably the reaction is carried out in the presence of a catalytic amount of benzoyl peroxide.

［式中、Ｒ’_５およびＲ’_６は式（ＩＩ）に関して上記したとおりである］
で示される化合物を式（ＸＩＩＩ）：

［式中、Ｒ’_４は式（ＩＩ）に関して上記したとおりである］
で示される化合物と反応させることによって調製される。 The compound of formula (VI) is conveniently of formula (VII):

[Wherein R ′ ₅ and R ′ ₆ are as described above for formula (II)]
A compound represented by the formula (XIII):

[Wherein R ′ ₄ is as described above for formula (II)]
It is prepared by reacting with a compound represented by

  The reaction between formulas (VII) and (XIII) is conveniently carried out using Pfitzinger reaction conditions (eg J. Prakt. Chem. 33, 100 (1886), J. Prakt. Chem. 38 , 582 (1888), J. Chem. Soc. 106 (1948) and Chem. Rev. 35, 152 (1944)). For example, in an alkanol solvent such as ethanol, any temperature that provides adequate formation of the desired product (but generally elevated temperature), such as the reflux temperature of the solvent, preferably potassium hydroxide or potassium In the presence of a base such as tert-butoxide. The Pfitzinger reaction can also be carried out at a temperature (provided that an appropriate rate of formation of the desired product is provided in the presence of an acid such as acetic acid or hydrochloric acid, as described in J. Med. Chem. 38, 906 (1995)). , Generally high temperature).

  The compounds of formula (VII) are known compounds or they are according to the methods used for the preparation of known compounds, for example J. Org. Chem. 21, 171 (1955); J. Org. Chem Prepared according to the method described in 21, 169 (1955).

［式中、Ｒ’_５およびＲ’_６は式（ＩＩ）に関して上記されたとおりである］
で示される化合物を式（ＸＶ）：

［式中、Ｒ’_４は式（ＩＩ）に関して上記したとおりである］
で示される化合物とオキソ酪酸の存在下で反応させることによって調製されうる。 Alternatively, the compound of formula (VI) is conveniently of formula (XIV)

[Wherein R ′ ₅ and R ′ ₆ are as described above for formula (II)]
A compound represented by the formula (XV):

[Wherein R ′ ₄ is as described above for formula (II)]
In the presence of oxobutyric acid.

The reaction between compounds of the formulas (XIV) and (XV) is conveniently carried out using Doebner reaction conditions (eg Chem. Ber. 29, 352 (1894); Chem. Revs. 35, 153, (1944); Chem. Soc. B, 1969, 805), for example, in an alcoholic solvent such as ethanol, at any temperature that provides a suitable rate of formation of the desired product (but generally high temperature) For example, at the reflux temperature of the solvent.
The compounds of formula (XIV) and (XV) are known compounds or they are prepared according to the methods used for the preparation of known compounds, for example as described in Vogel's Textbook of Practical Organic Chemistry. The

［式中、Ｒ’_４は式（ＩＩ）に関して上記したとおりであり、Ｔ_５は基：

（式中、Ｙはベンジル基などの保護基、特に、テルブトキシカルボニル基などの塩基性条件下で安定な保護基である）
である］
で示される化合物と反応させ、その後、所望により、例えば、脱水素化によって、いずれかの保護基を除去し、および／またはいずれかのＴ_５基を：

に変換することによって調製される。 In some other embodiments of the invention, the compound of formula (II) is a compound of formula (VII) as defined above:

Wherein R ′ ₄ is as described above for formula (II) and T ₅ is a group:

(In the formula, Y is a protecting group such as a benzyl group, particularly a protecting group that is stable under basic conditions such as a terbutoxycarbonyl group)
Is]
And then optionally removing any protecting group and / or removing any T ₅ group, for example by dehydrogenation:

It is prepared by converting into

  Reactions between compounds of formula (VII) and (VIII) are conveniently carried out under Pfitzinger reaction conditions (eg J. Prakt. Chem. 33, 100 (1886), J. Prakt. Chem. 38, 582 (1888) , J. Chem. Soc. 106 (1948) and Chem. Rev. 35, 152 (1944)), for example, to provide a suitable rate of formation of the desired product in an alkanolic solvent such as ethanol. It is carried out at any temperature (but generally elevated temperature), for example at the reflux temperature of the solvent, preferably in the presence of a base such as potassium hydroxide or potassium tert-butoxide.

の保護形態は、保護される基の特定の性質にしたがって変化するが、通常の化学的習慣にしたがって選択される。

The protected form of varies depending on the specific nature of the group to be protected, but is selected according to normal chemical practice.

に変換可能な基は、対象の基の特異的性質に依存して、通常の化学的慣習によって、必要であり、適当であると決定される基を包含する。

Groups that can be converted to include groups that are determined to be necessary and appropriate by normal chemical practice, depending on the specific nature of the group of interest.

の保護形態を脱保護するための適当な脱保護方法およびＴ_５を

に変換するための適当な変換方法は、Greene, T.W. and Wuts, P.G.M. Protective Groups in Organic Synthesis, John Wiley & Sons Inc. New York, 1991 (Second Edt.) または Kocienski, P.J. Protecting groups. George Thieme Verlag, New York, 1994 および Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; または Advanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992などの標準的テキストを参照にして、対象とする特定の基に依存する当該分野で通常用いられる方法であろう。

An appropriate deprotection method and T ₅ for the protected forms deprotection

Appropriate conversion methods for conversion to Greene, TW and Wuts, PGM Protective Groups in Organic Synthesis, John Wiley & Sons Inc. New York, 1991 (Second Edt.) Or Kocienski, PJ Protecting groups. George Thieme Verlag, With reference to standard texts such as New York, 1994 and Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; or Advanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992, It will be a method commonly used in the art depending on the particular group of interest.

［式中、Ｒ’_５は式（ＩＩ）に関して上記したとおりである］
で示される化合物から、式（ＩＸ）の化合物をまずハロゲン化、好ましくは、臭素化、またはメシル化し、その後、そのようにして形成されたハロゲン化またはメシル化産物を、Ｔ_５基を形成可能な化合物と反応させて式（ＶＩＩ）の所望の化合物を提供することによって、調製される。 The compound of formula (VIII) is of formula (IX):

[Wherein R ′ ₅ is as described above for formula (II)]
The compound of formula (IX) can be first halogenated, preferably brominated, or mesylated from the compound of formula I, and then the halogenated or mesylated product so formed can form a T ₅ group Prepared by reacting with a compound to provide the desired compound of formula (VII).

で示される基である場合、Ｔ_５基を形成可能な化合物は、上記の式（Ｖ）の化合物である。 T ₅ is

In the case of the group represented by the formula, the compound capable of forming the T ₅ group is the compound of the above formula (V).

  The halogenation of the compound of formula (IX) is suitably carried out using a conventional halogenating reagent. Mesylation is conveniently carried out with mesyl chloride in an inert solvent such as methylene dichloride, below room temperature, for example at 0 ° C., preferably in the presence of triethylamine.

であり、Ｔ_５基を形成可能な必要な化合物が上記の式（Ｖ）の化合物である場合、式（ＩＸ）の化合物のハロゲン化またはメシル化産物と式（Ｖ）の化合物との間の反応は、式（ＩＶ）および（Ｖ）の化合物間の反応に関して記載されたのと類似の条件下で行われる。 The reaction conditions between the compound of formula (IX) and the compound capable of forming a T ₅ group are conventional conditions determined by the particular nature of the reactants, eg, the required T ₅ is Base

And the required compound capable of forming a T ₅ group is a compound of formula (V) above, between the halogenated or mesylated product of the compound of formula (IX) and the compound of formula (V) The reaction is carried out under conditions similar to those described for the reaction between compounds of formula (IV) and (V).

Other compounds capable of forming the T ₅ group depend on the specific nature of T ₅ , but Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; and Advanced Organic Chemistry, March J, John A suitable compound determined by normal chemical practice with reference to standard texts such as Wiley & Sons, New York, 1992.

［式中、ａは式（ＶＩＩＩ）に関して上記したとおりである］
で示される化合物を式（ＸＩ）：

［式中、Ｒ’_５は式（ＩＩ）に関して上記したとおりである］
で示されるリチウム塩と反応させることによって調製されうる。 The compound of formula (IX) is represented by formula (X):

[Wherein a is as described above for formula (VIII)]
A compound represented by the formula (XI):

[Wherein R ′ ₅ is as described above for formula (II)]
It can be prepared by reacting with a lithium salt represented by

The reaction between the compounds of formulas (X) and (XI) can be carried out in an aprotic solvent such as diethyl-ether at any temperature that provides the desired product at a suitable rate of formation, usually from -10 ° C to- It can be performed at a low temperature such as 30 ° C., for example, at −20 ° C.
The compounds of formula (VII) are known compounds or they are the methods used for the preparation of known compounds, for example J. Org. Chem. 21, 171 (1955); J. Org. Chem. 21, 169 (1955).

  The compounds of formulas (X) and (XI) are known compounds or they are methods used to prepare known compounds, for example Krow GR in Organic Reactions, Vol 43, page 251, John Wiley & Sons Inc 1994 (for compounds of formula (X)) and Organometallics in Synthesis, Schlosser M. (Ed), John Wiley & Sons Inc. 1994 (for compounds of formula (XI)) The

［式中、Ｒ’_１、Ｒ’_２、Ｒ’_４、Ｒ’_５およびＲ’_６は各々、上記のＲ_１、Ｒ_２、Ｒ_４、Ｒ_５またはＲ_６であるか、あるいは各々、上記のＲ_１、Ｒ_２、Ｒ_４、Ｒ_５またはＲ_６に変換可能な基であり（但し、Ｒ’_２は性質上、芳香族ではない）、Ｌ_１は臭素原子などのハロゲン原子を示す］
で示される化合物を式（Ｖ）の化合物またはその保護形態またはそれに変換可能な基と反応させ、その後、下記の任意の工程：
（ｉ）Ｒ’_１、Ｒ’_２、Ｒ’_３、Ｒ’_４、Ｒ’_５およびＲ’_６のいずれか１つを各々、必要に応じてＲ_１、Ｒ_２、Ｒ_４、Ｒ_５またはＲ_６に変換して式（Ｉ）の化合物を得る；
（ｉｉ）式（Ｉ）の化合物を必要に応じて、式（Ｉ）の別の化合物に変換する；および
（ｉｉｉ）式（Ｉ）の化合物の塩および／またはその溶媒和物を調製する
の１以上を行うことを特徴とする調製法を提供する。 In another embodiment, the present invention provides a process for the preparation of a compound of formula (I) or a salt and / or solvate thereof, comprising formula (XVI):

[Wherein R ′ ₁ , R ′ ₂ , R ′ ₄ , R ′ ₅ and R ′ ₆ are each R ₁ , R ₂ , R ₄ , R ₅ or R ₆ above, respectively, or In which R ₁ , R ₂ , R ₄ , R ₅ or R ₆ can be converted (provided that R ′ ₂ is not aromatic in nature), and L ₁ represents a halogen atom such as a bromine atom]
Is reacted with a compound of formula (V) or a protected form thereof or a group convertible thereto, followed by any of the following steps:
(I) any one of R ′ ₁ , R ′ ₂ , R ′ ₃ , R ′ ₄ , R ′ ₅ and R ′ ₆ is R ₁ , R ₂ , R ₄ , R ₅ or Conversion to R ₆ to give a compound of formula (I);
(Ii) optionally converting a compound of formula (I) into another compound of formula (I); and (iii) preparing a salt of the compound of formula (I) and / or a solvate thereof. Provided is a method of preparation characterized by performing one or more.

The protected form of the compound of formula (V) will vary according to the particular nature of the group being protected, but will be selected according to normal chemical practice.
Groups that can be converted to R ₃ include groups that are required and determined to be suitable by normal chemical conventions, depending on the specific nature of R ₃ in question.

Suitable conversion method for converting a suitable deprotection methods and R _'3 for deprotecting protected forms of R ₃ to R ₃ are, Greene, TW and Wuts, PGM Protective Groups in Organic Synthesis, John Wiley & Sons Inc. New York, 1991 (Second Edt.) Or Kocienski, PJ Protecting groups. George Thieme Verlag, New York, 1994 and Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; or Advanced Organic Chemistry , March J, John Wiley & Sons, New York, 1992, and so on, depending on the specific group of interest, and would be the method commonly used in the field.

Suitable groups that can be converted to other groups include protected forms of the groups.
Suitably R ′ ₁ , R ′ ₂ , R ′ ₃ , R ′ ₄ , R ′ ₅ and R ′ ₆ are each R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ or protection thereof. The form is shown.

Suitable deprotection methods for deprotecting the protected forms of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ and R ′ ₁ , R ′ ₂ , R ′ ₃ , R ′ ₄ , R ′ Conversion methods for converting ₅ and R ′ ₆ to R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are as follows: Greene, TW and Wuts, PGM Protective Groups in Organic Synthesis, John Wiley & Sons Inc. New York, 1991 (Second Edt.) Or Kocienski, PJ Protecting groups. George Thieme Verlag, New York, 1994 and Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; or Advanced Organic Chemistry , March J, John Wiley & Sons, New York, 1992, and so on, depending on the particular group of interest, and would be the method commonly used in the field.

Suitably the reaction between compounds of formula (XVI) and (XVII) is carried out under conventional amination conditions, for example when L ₁ is a bromine atom, the reaction is conveniently The reaction is carried out in a protic solvent, such as tetrahydrofuran or dimethylformamide or acetonitrile, at any temperature that provides the desired product at a suitable rate of formation, usually at ambient temperature; preferably the reaction is triethylamine (TEA ), In the presence of sodium hydride or K ₂ CO ₃ .

  The compounds of formula (XVII) are known commercial compounds or they are analogous to methods used for the preparation of known compounds, for example the Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; Advanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992; J. Heterocyclic Chem. (1990), 27, 1559; Synthesis (1975), 135, Bioorg. Med. Chem. Lett. 1997), 7, 555, or Protective Groups in Organic Synthesis (second edition), Wiley Interscience, (1991) or other methods listed therein.

［式中、Ｒ’_１、Ｒ’_２、Ｒ’_４、Ｒ’_５およびＲ’_６は式（ＸＶＩ）に関して上記したとおりである］
で示される化合物の適当なハロゲン化によって調製される。 The compound of formula (XVI) is of formula (XVIII):

[Wherein R ′ ₁ , R ′ ₂ , R ′ ₄ , R ′ ₅ and R ′ ₆ are as described above with respect to formula (XVI)]
Prepared by appropriate halogenation of the compound

A suitable halogenating reagent is a conventional reagent depending on the nature of the halogen atom required, for example when L ₁ is bromine, a preferred halogenating reagent is N-bromosuccinimide (NBS).
Halogenation of the compound of formula (XVIII) is carried out under conventional conditions, for example bromination is desired in an inert solvent such as carbon tetrachloride CCl ₄ or 1,2-dichloroethane or CH ₃ CN. Preferably by treatment with NBS at any temperature providing a suitable rate of formation of the product, suitably at a high temperature such as 60 ° C. to 100 ° C., for example at 80 ° C .; The reaction is carried out in the presence of a catalytic amount of benzoyl peroxide.

Suitably, the compound of formula (XVIII) is a compound of formula (VI) as defined above or an active derivative thereof as defined above (wherein R ′ ₂ is not aromatic in nature). Can be prepared by reacting with.
As mentioned above, it is preferred that the compound of formula (VI) is present in the reaction mixture as an active derivative.

The reaction between the compound of formula (VI) or an active derivative thereof and the compound of formula (III) is carried out under conventional conditions appropriate for the particular compound selected. In general, when the compound of formula (VI) is present as an active derivative, the reaction is carried out using the same solvent and conditions used for the preparation of the active derivative, preferably the active derivative Is prepared in situ prior to forming the compound of formula (XVIII).
For example, the reaction between an active derivative of a compound of formula (VI) and a compound of formula (III) is:
(A) First, an acid chloride is prepared, and then the chloride and the compound of formula (III) are -70 to 50 ° C. (preferably in a suitable aprotic solvent such as methylene dichloride or tetrahydrofuran). By coupling in the presence of an inorganic or organic base at 20 ° C. to reflux temperature; or (b) a suitable condensing agent such as N, N′-carbonyldiimidazole (CDI) or carbodiimide For example, in the presence of dicyclohexylcarbodiimide (DCC) or N-dimethylaminopropyl-N′-ethylcarbodiimide, preferably N-hydroxybenzotriazole (HOBT) (HOBT) (in order to maximize yield and avoid racemization step) Synthesis, 453, 1972), or O-benzotriazol-1-yl-N, N, N ′, N′-tetramethyl. In the presence of tiluronium hexafluorophosphate (HBTU) in a volume ratio of aprotic solvent, for example a mixture of acetonitrile (MeCN) and tetrahydrofuran (THF), for example 1: 9-7: 3 (MeCN: THF) The compound of formula (VI) is reacted in the mixture at any temperature that provides a suitable rate of formation of the desired product, such as -70-50 ° C, preferably -10-25 ° C, eg 0 ° C. This may be done by treatment with a compound of formula (III).

A preferred reaction is illustrated in Scheme 2 below.
Scheme 2

  When utilizing the corresponding alkyl (eg, methyl or ethyl) ester of compound (VI), hydrolysis is required prior to conversion to compound (XVIII) in Scheme 2. Such hydrolysis can be carried out in an acidic condition such as 10-36% hydrochloric acid at a temperature range of 30-100 ° C.

［式中、Ｒ’_１およびＲ’_２は上記のとおりである］
で示される適当な鏡像異性的に純粋な第１アミンと反応させて、式（Ｉ’ａ）または（Ｉ’ｃ）：

［式中、Ｒ’_１、Ｒ’_２、Ｘ’、Ｒ’_４、Ｒ’_５およびＲ’_６は上記のとおりである］
で示される化合物を得ることによって得ることができる。 As noted above, compounds of formula (I) may exist in one or more stereoisomeric forms, and the methods of the invention can produce racemic as well as enantiomerically pure forms. Thus, a pure enantiomer of a compound of formula (I) is a compound of formula (II) as described above of formula (IIIa) or (IIIc):

[Wherein R ′ ₁ and R ′ ₂ are as described above]
By reaction with a suitable enantiomerically pure primary amine of formula (I′a) or (I′c):

[Wherein R ′ ₁ , R ′ ₂ , X ′, R ′ ₄ , R ′ ₅ and R ′ ₆ are as described above]
It can obtain by obtaining the compound shown by these.

［式中、Ｒ_１、Ｒ_２、Ｘ、Ｒ_４、Ｒ_５およびＲ_６は上記のとおりである］
で示される化合物に変換してもよい。 The compound of formula (I′a) or (I′c) is then converted to formula (Ia) or (Ic):

[Wherein R ₁ , R ₂ , X, R ₄ , R ₅ and R ₆ are as described above]
You may convert into the compound shown by these.

  Another method for separating optical isomers is to use a conventional fractional separation method, in particular a fractional crystallization method. Thus, the pure enantiomers of the compound of formula (I) are racemic compounds of formula (I) and optically active strong acid resolving agents such as camphorsulfonic acid, tartaric acid, O, O′-di-p-toluyltartaric acid or Obtained by fractional crystallization of diastereomeric salts formed by reaction with mandelic acid in a suitable alcoholic solvent such as ethanol or methanol, or a ketonic solvent such as acetone. The salt formation process should be carried out at 20-80 ° C, preferably 50 ° C.

Suitable conversion of one compound of formula (I) to a further compound of formula (I) is for example:
(I) converting the ketal to a ketone by mild acidic hydrolysis, for example using dilute hydrochloric acid;
(Ii) reducing the ketone to a hydroxy group by use of a borohydride reducing agent;
(Iii) by converting the carboxylic ester group to a carboxyl group using basic hydrolysis; and / or (iv) by reducing the carboxylic ester group to a hydroxymethyl group by use of a borohydride reducing agent. Conversion of one X group to another X group.

As described above, if necessary, R ′ ₁ , R ′ ₂ , X ′, which is usually a protected form of R ₁ , R ₂ , X, R ₄ , R ₅ or R ₆ as described above. , R ′ ₄ , R ′ ₅ and R ′ ₆ can be converted to R ₁ , R ₂ , X, R ₄ , R ₅ and R ₆ by appropriate conventional methods such as an appropriate deprotection method. Can be performed using various conditions.
In any of the above reactions, any reactive group in the substrate molecule may be, for example, Greene, TW and Wuts, PGM Protective Groups in Organic Synthesis, John Wiley & Sons Inc. New York, 1991 (Second Edt.) It will be apparent that protection and deprotection can be achieved according to conventional chemical practices such as those described in Kocienski, PJ Protecting groups. George Thieme Verlag, New York, 1994.

Suitable protecting groups in any of the above reactions are those conventionally used in the art. Thus, for example, suitable hydroxy protecting groups include benzyl or trialkylsilyl groups.
The methods for forming and removing such protecting groups are conventional methods appropriate for the molecule being protected. Thus, for example, a benzyloxy group may be prepared by treating a suitable compound with a benzyl halide, such as benzyl bromide, and then optionally converting the benzyl group conveniently to catalytic hydrogenation. Alternatively, it may be removed using a mild etherolysis reagent such as trimethylsilyl iodide or boron tribromide.

  A preferred method for preparing the compounds of the present invention is illustrated in Scheme 3.

試薬および条件：ａ）ＫＯＨ，ＥｔＯＨ；ｂ）塩化オキサリル，ＤＭＦ（ｃａｔ．）ＣＨ_２Ｃｌ_２；ｃ）（Ｓ）−シクロヘキシルエチルアミン，トリエチルアミン，ＣＨ_２Ｃｌ_２；ｄ）ＮＢＳ，過酸化ジベンゾイル，ＣＨ_３ＣＮ；ｅ）２−オキソ−ピペラジン，Ｎ，Ｎ−ジイソプロピルエチルアミン；ｆ）ＮａＨ，ヨード酢酸エチルエステル，ＤＭＳＯ；ｇ）１−メチルピペラジン，ＨＢＴＵ，Ｎ，Ｎ−ジイソプロピルエチルアミン，ＤＭＦ Scheme 3

. Reagents and conditions: a) KOH, EtOH; b ) oxalyl _{chloride, DMF (cat) CH 2 Cl} 2; c) (S) - cyclohexylethyl amine, _{triethylamine, CH 2 Cl 2; d)} NBS, dibenzoyl peroxide, CH ₃ CN; e) 2-oxo-piperazine, N, N-diisopropylethylamine; f) NaH, iodoacetic acid ethyl ester, DMSO; g) 1-methylpiperazine, HBTU, N, N-diisopropylethylamine, DMF

Thus, the reaction of 5-fluoroisatin and 3,5-difluoropropiophenone under basic conditions produces carboxylic acid 3-3. This is converted to the amide 3-4 via acid chloride and then by reaction with (S) -cyclohexylethylamine. Bromination using NBS followed by S _N 2 substitution of the bromide with 2-oxo-piperazine in the presence of Hunig's base produces compound 3-6. Alkylation of piperazinone nitrogen with iodoacetic acid ethyl ester in the presence of sodium hydride followed by hydrolysis under basic conditions provides acid 3-7. Acid 3-7 may be converted to the desired amide under standard conditions using 1-methylpiperazine and HBTU in the presence of 4-methylmorpholine in DMF, thereby obtaining amide 3-8.

  Alternatively, a compound represented by 4-7 below (wherein R4 is as described above) corresponding to compound 3-6 of Scheme 3 is prepared by the method described below in Scheme 4: Also good. Compound 4-7 can then be converted to a compound of formula (I) according to the last two steps of Scheme 3 (f and g).

試薬および条件：ａ）塩化オキサリル，ＤＭＦ（ｃａｔ．）ＣＨ_２Ｃｌ_２；（Ｓ）−シクロヘキシルエチルアミン，トリエチルアミン，ＣＨ_２Ｃｌ_２；ｂ）ＣＨ_３ＯＨ，ＮａＨ；ｃ）ＮＢＳ，過酸化ジベンゾイル，ＣＨ_３ＣＮ；ｄ）塩化オキサリル，ＤＭＦ（ｃａｔ．）ＣＨＣｌ_３；ｅ）２−オキソ−ピペラジン，Ｎ，Ｎ−ジイソプロピルエチルアミン；ｆ）（Ｒ４）Ｂ（ＯＨ）_２，Ｐｄ（０），ジオキサン−水 Scheme 4

Reagents and _conditions:. A) Oxalyl _{chloride, DMF (cat) CH 2 Cl} 2; (S) - cyclohexylethyl amine, _{triethylamine, CH 2 Cl 2; b)} CH 3 OH, NaH; c) NBS, dibenzoyl peroxide, CH ₃ CN; d) oxalyl chloride, DMF (cat.) CHCl ₃ ; e) 2-oxo-piperazine, N, N-diisopropylethylamine; f) (R4) B (OH) ₂ , Pd (0), dioxane-water

  Thus, treatment of acid 4-1 (for preparation, see Batt, DG et al. Bioorg. Med. Chem. Lett. 1998, 8, 1745) with oxalyl chloride provides two conversions: quinoline to 2-chloro. -Conversion of quinoline and acid to acid chloride is complete. The resulting acid chloride is reacted with (S) -1-cyclohexyl-ethylamine to give amide 4-2. Reaction with methanol provides 2-methoxy-quinoline 4-3. Radical bromination with N-bromosuccinimide (NBS) followed by treatment with oxalyl chloride and displacement with 2-oxo-piperazine then provides 4-6. (R4) A Suzuki cross-coupling reaction using B (OH) 2 gives compound 4-7.

As mentioned above, the compounds of formula (I) have useful pharmaceutical properties.
Accordingly, the present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof useful as an active therapeutic substance.
Accordingly, the present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof useful as an active therapeutic substance.

In particular, the present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the treatment or prevention of first and second conditions.
The present invention further provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.
The invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of first and second conditions.

  As noted above, the first condition is a respiratory disease such as chronic obstructive pulmonary disease (COPD), asthma, airway hyperreactivity, cough; inflammatory disease such as inflammatory bowel disease, psoriasis, connective tissue inflammation, Osteoarthritis, rheumatoid arthritis and inflammatory pain; neurological inflammation or peripheral neuropathy, allergies such as eczema and rhinitis; eye diseases such as ocular inflammation, conjunctivitis, spring conjunctivitis, etc .; skin diseases, skin disorders and pruritus such as skin Wheal and redness, contact dermatitis, atopic dermatitis, urticaria and other eczema-like dermatitis; adverse immunological reactions such as transplant rejection and disorders associated with immune enhancement or suppression, eg systemic Lupus erythematosus; gastrointestinal (GI) disorders and GI tract diseases, eg disorders associated with neuronal modulation of the viscera, eg ulcerative colitis, Crohn's disease, irritable colon Syndrome (IBS), gastroesophageal reflux disease (gastro-exophageous reflex disease) (GERD); including renal disorders; Disorders of the urinary incontinence and bladder function.

  As noted above, the second condition is a disorder of the central nervous system, such as anxiety, depression, psychosis and schizophrenia; a neurodegenerative disorder such as AIDS-related dementia, Alzheimer-type senile dementia, Alzheimer's disease, Down syndrome, Huntington's disease, Parkinson's disease, movement disorders, and convulsive disorders (eg, epilepsy); demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis and other neuropathological disorders such as , Diabetic neuropathy, AIDS-related neuropathy, chemotherapy-induced neuropathy and neuralgia; epilepsy disorders such as alcoholism; stress-related disabilities; reflex sympathetic dystrophy such as shoulder / hand syndrome; Disorders (eg food intake disorders); fibrosis and collagen diseases such as scleroderma and eosinophilic cirrhosis Blood flow disturbances caused by vasodilatation and vasospasm diseases such as angina, migraine and Reynaud disease and, for example, pain or nociceptive demands that contribute to or are associated with any of the above conditions, in particular, Includes pain transmission in migraine.

Such medicaments, and compositions of the present invention can be prepared by mixing a compound of the present invention with a suitable carrier. It may contain diluents, binders, fillers, disintegrating agents, flavoring agents, coloring agents, lubricants or preservatives in a conventional manner.
These conventional excipients may be used, for example, as in the preparation of known agent compositions for treating the condition.

Preferably, the pharmaceutical composition of the invention is in unit dosage form and in a form adapted for use in the medical or veterinary field. For example, such preparations may be in pack form with handwritten or printed instructions for use as a medicament in the treatment of the condition.
Suitable dosage ranges for the compounds of the present invention depend on the compound used and the patient's condition. It will also depend, inter alia, on the relationship of potency to absorbency and the frequency and route of administration.

The compounds or compositions of the present invention may be formulated for administration by any route, preferably in unit dosage form or in a form that can be taken by a human patient in a single dose. Advantageously, the composition is suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration. The preparation may be designed to give a slow release of the active ingredient.
The composition may be in the form of, for example, a tablet, capsule, sachet, vial, powder, granule, lozenge, reversible powder, or liquid preparation, such as a solution or suspension, or a suppository.

  Forms suitable for oral administration such as compositions are conventional excipients such as binders such as syrup, gum arabic, gelatin, sorbitol, tragacanth gum, or polyvinylpyrrolidone; bulking agents such as lactose, Sugars, corn starch, calcium phosphate, sorbitol or glycine; tablet lubricants such as magnesium stearate; disintegrants such as starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable hardeners ( setting agents), for example, sodium lauryl sulfate.

  Solid compositions can be obtained by conventional methods such as mixing, filling, tableting and the like. An iterative mixing operation may be used to distribute the active agent in the composition using a large amount of bulking agent. Where the composition is in the form of a tablet, powder or lozenge, any carrier suitable for formulating a solid pharmaceutical composition may be used, such as magnesium stearate, starch, glucose, lactose, sucrose, Rice flour and chalk. The tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating. The composition may also be in the form of an ingestible capsule, eg, gelatin containing the compound, optionally with a carrier or other excipient.

  Compositions for oral administration such as liquids may be in the form of, for example, emulsions, syrups, or elixirs, or provided as a dry product for reconstitution with water or other suitable vehicle prior to use. Good. Such liquid compositions can be prepared using conventional additives such as suspending agents such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fats; emulsifiers such as lecithin. Sorbitan monooleate, or gum arabic; edible oils such as almond oil, fractionated coconut oil, oily esters such as esters of glycerin, or propylene glycol, or aqueous solutions including ethyl alcohol, glycerin, water or saline Or a non-aqueous vehicle; preservatives such as methyl or propyl p-hydroxybenzoate or sorbic acid; and, if desired, conventional flavors or colorants.

  The compounds of the present invention may also be administered by a parenteral route. According to routine pharmaceutical practice, the composition can be formulated for rectal administration, eg, as a suppository. They are also injectable in aqueous or non-aqueous solutions, suspensions or emulsions in pharmaceutically acceptable liquids such as pyrogen-free sterile water or parenterally acceptable oils or liquid mixtures. It can be formulated to provide in form. The liquid contains bacteriostatic agents, antioxidants or other preservatives, buffers or solutes that make the solution isotonic with blood, thickeners, suspending agents or other pharmaceutically acceptable additives. It may be. Such forms can be used in unit dosage forms such as ampoules or disposable injection devices, or in multiple dosage forms such as bottles from which appropriate dosages are drawn, or solid or concentrated forms that can be used to prepare injectable formulations. Will be provided in the product.

The compounds of the present invention can also be administered by inhalation via the nasal or oral route. Such administration can be effected, if desired, using, for example, a spray formulation comprising a compound of the present invention and a suitable carrier suspended in a hydrocarbon propellant.
A preferred spray formulation comprises finely divided compound particles in combination with a surfactant, solvent or dispersant to prevent settling of suspended particles. Preferably, the compound particle size is about 2-10 microns.
A further mode of administration of the compounds of the present invention involves transdermal delivery using a skin patch formulation. A preferred formulation includes a compound of the present invention dispersed in a pressure sensitive adhesive that adheres to the skin so that the compound can be released from the adhesive and delivered to the patient through the skin. It becomes. For constant rate percutaneous absorption, pressure sensitive adhesives known in the art such as natural rubber or silicone can be used.

As noted above, the effective dosage of a compound depends on the particular compound used, the condition of the patient, and the frequency and route of administration. The unit dose will generally contain 20 to 1000 mg, preferably 30 to 500 mg, in particular 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 mg. The composition may be administered one or more times a day, for example 2, 3 or 4 times a day, and the total daily dose for a 70 kg adult is usually in the range of 100 to 3000 mg. Alternatively, a unit dose contains 2-20 mg of active ingredient, optionally administered multiple times to give the above daily dose.
When administered in accordance with the present invention, unacceptable toxicological effects are not expected using the compounds of the present invention.

The present invention is also a method for the treatment and / or prevention of first and second conditions in mammals, particularly humans, which is effective for mammals in need of such treatment and / or prevention. A method is provided which comprises administering a toxic pharmaceutically acceptable amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
The activity of the compounds of the present invention as NK ₃ ligands is indicated by radiolabeled NK ₃ ligands, [ ¹²⁵ I]-[Me-Phe ⁷ ] -NKB or [ ³ H]-, for guinea pig and human NK ₃ receptors. Determined by ability to inhibit Senktide binding (Renzetti et al, 1991, Neuropeptide, 18, 104-114; Buell et al, 1992, FEBS, 299 (1), 90-95; Chung et al, 1994, Biochem Biophys. Res. Commun., 198 (3), 967-972).

The binding assay used is the individual compound required to reduce [ ¹²⁵ I]-[Me-Phe ⁷ ] -NKB and [ ³ H] -Senktide specific binding to the NK ₃ receptor by 50% at equilibrium conditions. Allows the determination of the concentration of (IC50).
The binding assay provides an average IC ₅₀ value of 2-5 separate experiments performed in duplicate or triplicate for each compound tested. The most potent compounds of the invention exhibit IC ₅₀ values of 10-1000 nM. The NK ₃ -antagonist activity of the compounds of the present invention is determined by guinea pig ileum (Maggi et al, 1990, Br. J. Pharmacol., 101, 996-1000) and rabbit isolated iris sphincter (Hall et al., 1991, Eur. J. Pharmacol., 199, Senktide induced contractions and human NK ₃ receptor mediated ^{Ca ++} mobilization 9-14) (Mochizuki et al, 1994 , J. Biol. Chem., 269, inhibits 9651-9658) Determined by ability. Guinea pig and Usagiin vitro functional assay for each compound tested, providing a mean K _B value of 3-8 separate experiments, here, K _B is twice the right in the concentration-response curve of Senktide The concentration of the individual compound required to shift. The human receptor functional assay allows the determination of the concentration of individual compounds (IC ₅₀ values) required to reduce Ca ⁺⁺ mobilization induced by the agonist NKB by 50%. In the assay, the compounds of the invention act as antagonists.

The activity of the compounds of the present invention as NK-2 ligands is the ability to inhibit the binding of radiolabeled NK-2 ligand, [ ¹²⁵ I] -NKA or [ ³ H] -NKA to the human NK-2 receptor. (Aharony et al, 1992, Neuropeptide, 23, 121-130).
The binding assay used is the concentration of the individual compounds required to reduce [ ¹²⁵ I] -NKA and [ ³ H] -NKA specific binding to the NK-2 receptor by 50% at equilibrium conditions (IC ₅₀ ).

The binding assay provides an average IC ₅₀ value of 2-5 separate experiments performed in duplicate or triplicate for each compound tested. The most potent compounds of the present invention exhibit IC ₅₀ values in the range 1-1000 nM, for example 1-100 nM. The NK-2-antagonist activity of the compounds of the present invention is determined by their ability to inhibit human NK-2 receptor-mediated Ca ⁺⁺ mobilization (Mochizuki et al, 1994, J. Biol. Chem., 269, 9651- 9658). The human receptor functional assay allows the determination of the concentration of individual compounds (IC ₅₀ values) required to reduce Ca ⁺⁺ mobilization induced by the agonist NKA by 50%. In the assay, the compounds of the invention act as antagonists.

The therapeutic potential of the compounds of the present invention in the treatment of disease states can be assessed using a rodent disease model.
As mentioned above, compounds of formula (I) are also considered useful as diagnostic tools. Thus, the present invention provides compounds of formula (I) that are useful as diagnostic tools for assessing the extent to which neurokinin-2 and neurokinin-3 receptor activity (normal, overactivity or underactivity) is related to patient symptoms. Includes compounds. Such use may be of formula (I) as an antagonist of said activity, including, but not limited to, tachykinin agonist-induced inositol phosphate turnover or electrophysiological activation of a cell sample obtained from a patient. ). In the presence or absence of a compound of formula (I), such a comparison of activity will disclose the degree of involvement of the NK-2 and NK-3 receptors in mediating agonist effects in the tissue.

Description and Experiments Nuclear magnetic resonance spectra were recorded at 400 MHz using a Bruker AC400 spectrometer. CDCl ₃ is deuteriochloroform, DMSO-d ₆ is hexadeuteriodimethylsulfoxide, and CD ₃ OD is tetradeuteriomethanol. Chemical shifts are reported in parts per million () from internal standard tetramethylsilane to low magnetic fields. Abbreviations for NMR data are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet doublet, dt = triplet doublet, app = apparent, br = Wide. J indicates the NMR coupling constant measured at Hertz. Continuous wave infrared (IR) spectra were recorded with a Perkin-Elmer 683 infrared spectrometer, and Fourier transform infrared (FTIR) spectra were recorded with a Nicolet Impact 400D infrared spectrometer. IR and FTIR spectra are recorded in transmission mode, and band positions are reported as reciprocal wavenumbers (cm ⁻¹ ). Mass spectra were performed on either a VG70FE, PE Six API III or VG ZAB HF instrument using fast atom bombardment (FAB) or electrospray (ES) ionization techniques. Elemental analysis was obtained using a Perkin-Elmer 240C elemental analyzer. Melting points are measured in a Thomas-Hoover melting point apparatus and no correction is made. All temperatures are reported in degrees Celsius.

  Analtech silica gel GF and E.I. Merck silica gel 60 F-254 thin layer plates were used for thin layer chromatography. Both flash and gravity chromatography were performed on E. coli. Performed on Merck Kieselgel 60 (230-400 mesh) silica gel.

In the synthesis examples below, the temperature is in degrees Celsius (° C.). Unless otherwise noted, all starting materials were commercially available. For reverse phase HPLC (unless otherwise noted) 50 × 20 mm I.D. D. YMC CombiPrep ODS-A column at 20 mL / min, 10 min, with _{10% CH 3 CN~90% CH 3} CN gradient in the _{H 2} O, at the end of each run, _{H 2} O in 90% CH ₃ Maintained with CN for 2 minutes. Without further contrivance, those skilled in the art will be able to use the above to utilize the present invention to its full extent. These examples are set forth to illustrate the invention and are not intended to limit its scope. In the following, what is secured by the inventors refers to the claims.

Example 1
2- (3,5-Difluoro-phenyl) -6-fluoro-3- {4- [2- (4-methyl-piperazin-1-yl) -2-oxo-ethyl] -3-oxo-piperazine-1 -Ylmethyl} -quinoline-4-carboxylic acid ((S) -1-cyclohexyl-ethyl) -amide 1a) {4- [4-((S) -1-cyclohexyl-ethylcarbamoyl) -2- (3,5 -Difluoro-phenyl) -6-fluoro-quinolin-3-ylmethyl] -2-oxo-piperazin-1-yl} -acetic acid 2- (3,5-difluoro-phenyl) -6-fluoro-3- (3- Oxo-piperazin-1-ylmethyl) -quinoline-4-carboxylic acid ((S) -1-cyclohexyl-ethyl) -amide (3- (3-oxo-piperazin-1-ylmethyl) -2-thiophene- A solution of 2-yl-quinoline-4-carboxylic acid ((S) -1-cyclohexyl-ethyl) -amide-prepared in a similar manner to WO 0244165) (400 mg, 0.76 mmol) in DMSO (3 mL) at room temperature. And mixed with NaH (37 mg, 60% in mineral oil, 0.91 mmol). The resulting mixture was stirred for 3 minutes and mixed with iodo-acetic acid ethyl ester (0.1 mL, 0.91 mmol). After stirring for 1 hour, the reaction mixture was purified by reverse phase HPLC (Gilson) to give the title compound (75 mg, 17%). MS (ES) m / z 584 (M + H) ⁺

1b) 2- (3,5-Difluoro-phenyl) -6-fluoro-3- {4- [2- (4-methyl-piperazin-1-yl) -2-oxo-ethyl] -3-oxo-piperazine -1-ylmethyl} -quinoline-4-carboxylic acid ((S) -1-cyclohexyl-ethyl) -amide {4- [4-((S) -1-cyclohexyl-ethylcarbamoyl) -2- (3,5 -Difluoro-phenyl) -6-fluoro-quinolin-3-ylmethyl] -2-oxo-piperazin-1-yl} -acetic acid (30 mg, 0.051 mmol) in DMF (1 mL) was added 1-methyl-piperazine ( 1 drop, excess), mixed with HBTU (20 mg, 0.052 mmol) and diisopropylethylamine (3 drops, excess). After stirring for 1 hour, the reaction mixture was purified by reverse phase HPLC to give the title compound (10 mg, 29%). MS (ES) m / z 666 (M + H) ⁺

Example 2
2- (3,5-Difluoro-phenyl) -6-fluoro-3- [3-oxo-piperidin-1-yl-ethyl) -piperazin-1-ylmethyl] -quinoline-4-carboxylic acid ((S)- 1-cyclohexyl-ethyl) -amide title compound is prepared according to the procedure of 1b with piperidine and {4- [4-((S) -1-cyclohexyl-ethylcarbamoyl) -2- (3,5-difluoro-phenyl) Prepared in 48% yield from -6-fluoro-quinolin-3-ylmethyl] -2-oxo-piperazin-1-yl} -acetic acid. MS (ES) m / z 651 (M + H) ⁺

Example 3
6-Fluoro-2- (4-fluoro-phenyl) -3- [4- (2-morpholin-4-yl-2-oxo-ethyl) -3-oxo-piperazin-1-ylmethyl] -quinoline-4- Carboxylic acid ((S) -1-cyclohexyl-ethyl) -amide 3a) {4- [4-((S) -1-cyclohexyl-ethylcarbamoyl) -6-fluoro-2- (4-fluoro-phenyl)- Quinolin-3-ylmethyl] -2-oxo-piperazin-1-yl} -acetic acid 6-fluoro-3- (3-oxo-piperazin-1-ylmethyl) -2- (4-fluoro-phenyl) -2-yl -Quinolin-4-carboxylic acid ((S) -1-cyclohexyl-ethyl) -amide (3- (3-oxo-piperazin-1-ylmethyl) -2-thiophen-2-yl-quinoline-4- A solution of carboxylic acid ((S) -1-cyclohexyl-ethyl) -amide-amide prepared in a similar manner to WO 0244165) (80 mg, 0.168 mmol) in DMF (0.5 mL) at room temperature with NaH (12 0.1 mg, 60% in mineral oil, 0.504 mmol). The resulting mixture was stirred for 3 minutes and mixed with bromo-acetic acid ethyl ester (0.0186 mL, 0.168 mmol). After stirring for 1 hour, the reaction mixture was purified by reverse phase HPLC (Gilson) to give the title compound (85 mg, 90%). MS (ES) m / z 565 (M + H) ⁺

3b) 6-Fluoro-2- (4-fluoro-phenyl) -3- [4- (2-morpholin-4-yl-2-oxo-ethyl) -3-oxo-piperazin-1-ylmethyl] -quinoline- 4-carboxylic acid ((S) -1-cyclohexyl-ethyl) -amide {4- [4-((S) -1-cyclohexyl-ethylcarbamoyl) -6-fluoro-2- (4-fluoro-phenyl)- A solution of 2-yl-quinolin-3-ylmethyl] -2-oxo-piperazin-1-yl} -acetic acid (23 mg, 0.0407 mmol) in DMF (0.5 mL) was transformed into morpholine (0.0036 mL, 0.0407 mmol). , HBTU (15.4 mg, 0.0407 mmol) and 4-methyl-morpholine (0.0089 mL, 0.0814 mmol). After stirring for 1 hour, the reaction mixture was purified by reverse phase HPLC to give the title compound (14 mg, 54%). MS (ES) m / z 634 (M + H) ⁺ ;
¹ H-NMR (CDCl ₃ ) δ 1.18 (m, 6H), 1.30 (d, J = 6.7 Hz, 3H), 1.50 (m, 1H), 1.79 (m, 4H), 2.54 (m, 2H), 3.04 (m, 2H), 3.23 (m, 2H), 3.45 (m, 2H), 3.59 (m, 2H), 3.68 (m, 4H), 3.80 (m, 2H), 4.05 (d, J = 5.8 Hz, 1H), 4.14 (d, J = 5.8 Hz, 1H), 4.24 (m, 1H), 6.95 (s, br, 1H), 7.20 (m, 2H), 7.54 (m, 3H), 7.65 (m, 1H ), 8.13 (m, 1H)

Example 4
6-Fluoro-2- (4-fluoro-phenyl) -3- {4- [2- (4-methyl-piperazin-1-yl) -2-oxo-ethyl] -3-oxo-piperazin-1-ylmethyl } -Quinoline-4-carboxylic acid ((S) -1-cyclohexyl-ethyl) -amide The title compound is converted to {4- [4-((S) -1-cyclohexyl-ethylcarbamoyl)- Prepared from 6-fluoro-2- (4-fluoro-phenyl) -2-yl-quinolin-3-ylmethyl] -2-oxo-piperazin-1-yl} -acetic acid in 60% yield.
MS (ES) m / z 647 (M + H) ⁺ ;
¹ H-NMR (CDCl ₃ ) δ 1.18 (m, 6H), 1.30 (d, J = 6.7 Hz, 3H), 1.50 (m, 1H), 1.79 (m, 4H), 2.30 (s, 3H), 2.41 (m, 4H), 2.54 (m, 2H), 3.00 (m, 2H), 3.18 (m, 2H), 3.44 (m, 2H), 3.59 (m, 2H), 3.80 (m, 2H), 4.04 ( d, J = 5.8 Hz, 1H), 4.15 (d, J = 5.8 Hz, 1H), 4.23 (m, 1H), 6.90 (m, br, 1H), 7.20 (m, 2H), 7.54 (m, 3H ), 7.65 (m, 1H), 8.13 (m, 1H)

Example 5
6-Fluoro-2- (4-fluoro-phenyl) -3- [3-oxo-4- (2-oxo-2-pyrrolidin-1-yl-ethyl) -piperazin-1-ylmethyl] -quinoline-4- Carboxylic acid ((S) -1-cyclohexyl-ethyl) -amide title compound is converted according to the procedure of 3b to {4- [4-((S) -1-cyclohexyl-ethylcarbamoyl) -6-fluoro-2- Prepared from (4-fluoro-phenyl) -2-yl-quinolin-3-ylmethyl] -2-oxo-piperazin-1-yl} -acetic acid in 58% yield. MS (ES) m / z 618 (M + H) ⁺ ;
¹ H-NMR (CDCl ₃ ) δ 1.18 (m, 6H), 1.29 (d, J = 6.7 Hz, 3H), 1.50 (m, 1H), 1.84 (m, 6H), 1.97 (m, 2H), 2.54 (m, 2H), 3.04 (m, 2H), 3.27 (m, 2H), 3.43 (m, 4H), 3.80 (m, 2H), 3.95 (d, J = 6.0 Hz, 1H), 4.08 (d, J = 6.0 Hz, 1H), 4.23 (m, 1H), 7.10 (m, br, 1H), 7.18 (m, 2H), 7.51 (m, 3H), 7.65 (m, 1H), 8.13 (m, 1H )

Claims (12)

Formula (I):

[Where:
R ₁ is H or substituted or unsubstituted (C _1-6 ) alkyl;
R ₂ is substituted or unsubstituted aryl, (C _3-7 ) cycloalkyl, or heterocycle;
R ₃ is H or substituted or unsubstituted (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, aryl or heterocycle;
A is NR ₈ or O;
R ₈ is H or substituted or unsubstituted (C _1-6 ) alkyl;
R ₄ is substituted or unsubstituted phenyl;
R ₅ is from the list consisting of H or alkyl, alkenyl, aryl, alkoxy or hydroxylated derivatives thereof, hydroxy, halogen, nitro, cyano, carboxy, alkylcarboxy, alkylcarboxyalkyl, haloalkyl, amino or mono- or dialkylamino Up to three independently selected substituents; or R ₅ represents a bridging moiety arranged to bridge two adjacent ring atoms, wherein the bridging moiety is alkyl or dioxy Including alkylene;
R ₆ is H or halo;
R ₇ is oxo;
n is 1-4]
A compound represented by The compound according to claim 1, wherein R ₁ is methyl. _2. A compound according to claim 1, wherein R2 is substituted or unsubstituted phenyl or cyclohexyl. The compound according to claim 1, wherein R ₃ is methyl, substituted or unsubstituted morpholino, piperazine, pyrrole, piperidine, thiophene, imidazole or pyrazole. The compound according to claim 1, wherein R ₈ is H or methyl. The compound according to claim 1, wherein R ₄ is phenyl substituted with 1 to 3 fluorines. The compound according to claim 1, wherein R ₅ is H or fluoro. The compound according to claim 1, wherein R ₆ is H or fluoro. 2- (3,5-Difluoro-phenyl) -6-fluoro-3- {4- [2- (4-methyl-piperazin-1-yl) -2-oxo-ethyl] -3-oxo-piperazine-1 -Ylmethyl} -quinoline-4-carboxylic acid ((S) -1-cyclohexyl-ethyl) -amide;
2- (3,5-Difluoro-phenyl) -6-fluoro-3- [3-oxo-piperidin-1-yl-ethyl) -piperazin-1-ylmethyl] -quinoline-4-carboxylic acid ((S)- 1-cyclohexyl-ethyl) -amide;
6-Fluoro-2- (4-fluoro-phenyl) -3- [4- (2-morpholin-4-yl-2-oxo-ethyl) -3-oxo-piperazin-1-ylmethyl] -quinoline-4- Carboxylic acid ((S) -1-cyclohexyl-ethyl) -amide;
6-Fluoro-2- (4-fluoro-phenyl) -3- {4- [2- (4-methyl-piperazin-1-yl) -2-oxo-ethyl] -3-oxo-piperazin-1-ylmethyl } -Quinoline-4-carboxylic acid ((S) -1-cyclohexyl-ethyl) -amide; and 6-fluoro-2- (4-fluoro-phenyl) -3- [3-oxo-4- (2-oxo) 2-pyrrolidin-1-yl-ethyl) -piperazin-1-ylmethyl] -quinoline-4-carboxylic acid ((S) -1-cyclohexyl-ethyl) -amide; or a pharmaceutically acceptable salt thereof. Item 1. The compound according to Item 1. Formula (II):

Or the active derivative thereof is represented by the formula (III):

[Wherein R ′ ₁ and R ′ ₂ are R ₁ and R _{2 as} defined for formula (I), or are groups or atoms, respectively, convertible to R ₁ and R ₂ ]
Is reacted with a compound of formula (Ic):

[Wherein R ′ ₁ , R ′ ₂ , X ′, R ′ ₄ , R ′ ₅ and R ′ ₆ are as described above]
And then the following optional steps:
(I) As necessary, any one of R ′ ₁ , R ′ ₂ , X ′, R ′ ₄ , R ′ ₅ and R ′ ₆ is R ₁ , R ₂ , X, R ₄ , R Conversion to ₅ and R ₆ to give a compound of formula (I);
Performing one or more of (ii) converting a compound of formula (I) to another compound of formula (I); and (iii) preparing a salt of the compound of formula (I) and / or a solvate thereof. A process for the preparation of a compound of formula (I) according to claim 1 or a salt and / or a solvate thereof.   A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.   A method for treating respiratory diseases in mammals, comprising administering an effective amount of the compound of claim 1.